CA1055948A - Methods for the preparation of phenyl-benzoic acid derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Processes are provided for the preparation of a series of new compounds, their pharmaceutically acceptable, non-toxic salts, and their pharmaceutically acceptable, non-toxic esters, which compounds are valuable in the human and veterinary practice.
Such compounds have the general formula:

Description

" lQS55~48 This inventi.on relates to processes for the production of a series of new compounds, their pharmaceutically acceptable, non-toxic salts, and their pharmaceutically acceptable, non-toxic esters, and to the compounds so formed.
The compounds of one aspect of this invention have the general formula:

YRl .
Ar ~

H2NO2S ~ COOH
in which Rl represents a straight or branched unsubstituted alkyl containing 1 to 6 carbon atoms; a straight or branched unsubstituted alkenyl containing 2 to 6 carbon atoms; a straight or branched unsubstituted alkynyl containing 2 to 6 carbon atoms; or a methyl or ethyl radical substituted with phenyl, furyl, thienyl or pyridyl radical; Ar stands for a phenyl radical, Y stands for O,S, or NH;
and YRl is placed in the 2- or 3-position; or the pharmaceutically t acceptable, non-toxic salts thereof; or the pharmaceutically accept- F
able, non-toxic esters thereof, with cyanomethanol, benzyl alcohol or Cl - C6 alkanols.

In particular, Rl may represent, e.g., a methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert. butyl radical, or one of the differ-ent isomeric pentyl, or hexyl radicals, an alkenyl or alkynyl radical, e.g., an allyl, or propargyl radical, a benzyl or phenethyl radical, a

2-, 3-, or 4-pyridylmethyl, 2- or 3-furylmethyl, 2- or 3-thienylmethyl, thiazolylmethyl, or imidazolylmethyl radical; or one of the correspon-ding ethyl radicals.
Of particular ~alue are the compounds in which Rl is selected from the group consisting of straight or branched C3-C5 alkyl radicals, and a methyl radical being substituted with phenyl, furyl, thienyl, and 30 pyridyl, and the correspondingly substituted ethyl radicals.
B ~ -2-~

"` 1055948 The substituents Rl and Ar of formula I can be further sub-stituted in different positions with different groups, such as, for ....,.

Pxample, one or more halogen atoms, e,g. chlorine or bromine atoms, lower alkyl, halo-lower alkyl, e.~. trifluoromethyl; amlno groups, optionally being alkylated or acylated; hydroxy groups, which may be etherified, e.g. lower alkoxy, such as, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy or isobutoxy, or esterified with lower aliphatic carboxylic acids, such as, for example, lower alkanoic acids. e.g., acetic, propionic or pivalic acid, lower alkenoic acids, e.g. acrylic or -methacrylic acid, or with lower aliphatic dicarboxylic acids, e.g.
oxalic, malonic, succinic, glutaric, adipic, maleic or fumaric acid or their acid esters with lower alkanols, e.g. methanol or ethanol; or etherified mercapto groups such as, for example, methylthio, ethylthio, isopropylthio, butylthio or isobutylthio radicals.
Whenever the expression "lower alkyl" is used in the foregoing and in the following it stands for a straight or branched alkyl radical with ~rom 1 to 6 carbon atoms in the chain.
By another aspect of this invention, a process is provided for producing a compound of the formula ~ ~ Ar~yRl ~herein Rl represents a straight or branched unsubstituted al~yl containing 1 to 6 carbon atoms; a straight or branched unsubstituted alkenyl containing 2 to 6 carbon atoms; a straight or branched unsubstituted alkynyl containing 2 to 6 carbon atoms; or a methyl 5 or ethyl radical substituted with phenyl, furyl, thienyl or pyridyl radical; Ar comprises a phenyl radical, Y comprises 0, S, or NH;
YRl is placed in the 2- or 3-position.; or pharmaceutically acceptable, non-toxic salts thereof; or pharmaceutically acceptable, non~toxic esters thereof with cyano methanol, benzyl al¢ohol and Cl - C6 B~ ~ 3 alkanols; which process comprises one of the following reactions:
(a) reacting a compound of the general formula t 105~948 -or a salt or an ester thereof, wherein Rl and Y have the meanings defined above, and Hal comprises halogen, with ammonia; or (b) reacting a com-pound of the general formula YH

: 10 Ar ~ ~OOH

or an ester thereof, in which Ar and Y have the meanings defined above, with a compound of the formula RlZ,wherein Rl has the meaning defined above, and Z comprises a halogen atom, or an alkyl- or arylsulfonyloxy r group, or with a di-Rl-sulphate, or a diazo compound of the formula RlN2 or a quaternary ammonium compound of the formula RlN (Alk)3 wherein Rl is as defined above, and Alk comprises alkyl having from 1 to 6 carbon atoms; or (c) subjecting a compound of the formula Z0 Ar ~ ~ H

wherein Ar is as defined above and Y comprises NH, to a reductive alkylation using an aldehyde corresponding to Rl as defined above in having the same carbon atom content.
By still another ~spect of this invention, a process is pro-vided for producing a compound of the general formula Ia, YRl

3~ Ia H2No2s ~ COOH

3~ .

105594~

in which Rl represents a straight or branched unsubstituted alkyl contain~ng 1 to 6 carbon atoms; a straight or branched unsubstituted alkenyl containing 2 to 6 carbon atoms; a straight or branched ~r unsubstituted alkynyl containing 2 to 6 carbon atoms; or a methyl or ~thyl radical substituted with phenyl, furyl, thienyl or pyridyl radical; Y stands for 0, S, or NH; or pharmaceutically acceptable, non-toxic salts thereof; or pharmaceutically acceptable, non-toxic esters thereof with cyano methanol, benzyl alcohol and Cl - C6 alkanols; which comprises one -4a-. ~ "~,.

10555~48 of the following reactions: (a) reacting a compound of the general formula IIa YRl ~ lla HalO2S . COOH

or a salt or an ester thereof, in which Rl and Y have the meanings defined above, and Hal stands for halogen, with ammonia; (b) treating a compound of the general formula VIIIa - YH

VIlIa H2NO2S ~ COOH

or an ester thereof, in which Y has the meaning defined above with a com-pound RlZ, in which Rl has the meaning defined above, and Z stands for a halogen atom, or an alkyl- or arylsulfonyloxy group, or with a di-Rl-sulphate, a diazo compound of the for~ula ~N2, or a quaternary ammonium compound of the formula ~N (Alk)3, Rl being defined as above and Alk standing for alkyl with from 1 to 6 carbon atoms; or (c) subjecting a compound of the general fo-mula VIIIa, in which Y stands for NH, to a reductive alkylation using an aldehyde corresponding to Rl in having the same carbon atom content.

According to one embodiment of this aspect of the invention, the compounds are prepared according to the following reaction scheme Ar ~ 1 A ~

HalO2S COOH H2NO2S . COOH

II I -105594~
in which formulae the substituents Rl, Ar and Y are as defined before, and Hal stands for a halogen atom, preferabl~ chlorine. The compound of formula II is reacted with ammonia, preferably in the presence of a suitable solvent, such as, for example, water, or with a compound cap-able of liberating ammonia, such as, for example, ammonium salts or hexamethylenetetramine. The isolation of the compounds of formula I can be performed by means of well-known standard procedures.
When esters of the compounds of the formular II are used in the reaction, the compounds of the formula I are obtained as esters, or in some cases due to an aminolysis as amides. The corresponding free acids may, optionally, be obtained by a subsequent saponification. In case of the desired product being an ester and the starting material of fo Dula II being the free acid, an esterification can be performed either before or after the amidation process.
The starting compounds of formula II can e.g. be prepared from compounds of formula III

Ar~l III

in which ~ , Ar and Y are as defined above. By subjecting these com-pounds to a diazotation followed by the well-known Meerwein-reaction, the corresponding 5-halosulfonyl derivatives of formula II are obtained.
The compounds of formula III can be prepared in different manners depending on the meaning and place of Y.
The starting materlals of formula III in which YRl is placed in the 3-position are prepared from 3,5-dinitro-4-halobenzoic acid or preferably from an alkyl ester thereof which is subjected to an Ullmann reaction by reacting it with a substituted or unsubstituted halobenzene, preferably an iodo-benzene or a bromobenzene in the presence of copper powder. Due to the high reactivity of the halogen atom between the two 1055~48 nitro groups the reaction can be performed at a rather moderate tempera-ture giving high yields of the unsymmetric biphenyl de~ivative of the formula ::' N02 Ar ~ IV

or an ester thereof.
A partial reduction of one of the nitro groups of the 4-Ar-3,5-dinitrobenzoic acid obtained by means of a reducing agent, such as, for example, an alkali dithionite, if necessary after saponification of the corresponding ester, yields the 3-amino-4-Ar-5-nitrobenzoic acid of the formula:

Ar ~ V

O2N ~ COOH
.

R2 being an amino radical and Ar being as defined above.
The 3-amino group in the compounds of formula V is diazotized, and the diazonium salt solution is heated~ if necessary under acidic conditions, to give the corresponding 4-Ar-3-hydroxy-5-nitrobenzoic acid of formula V, R2 being a hydroxy group. When the corresponding 3-mercapto derivative is desired, the above-mentioned diazonium salt, if convenient after isolation and purification as, e.g. a diazoniumtetra-fluoroborate or a diazoniumchloride, is reacted with e.g. potassium ethyl xanthate or with potassium thiocyanate in the presence of copper thiocyanate or with an alkali disulfide followed by either a saponifica-tion or a reduction, dependent on the reactant used in the process.
Thereby a compound of formula V, R2 being a mercapto group, is obtained.
In a next step the compound of formula V, R2 being an amino, ~055~48 a hydroxy or a mercapto group, is alkylated by treatin8 the acid or one of its esters with a compound RlZ, in which Rl is as above defined and Z stands for a halogen atom, or an alkyl- or arylsulfonyloxy group or with a di-Rl-sulphate, a diazo compound of the formula RlN2, or a quaternary ammonium compound of the formula RlN+(Alk)3, in which Rl has the above meaning and Alk ctands for alkyl with from 1 to 4 carbon atoms, resulting in a compound of formula VI

Ar IRl ~ VI

A ~ COOH

in which Y stands for NH, O, S; A is a N02 group, and in which ~ and Ar have the above meanings.
For the preparation of the starting material of formula III in which Y stands for CH2, the above-mentioned diazonium salt prepared from a compound of formula V (R2=NH2) is reacted with the appropriate alkene in known manner, the resulting 3-alkene-4-Ar-5-nitrobenzoic acid there-after being hydrogenated to the compound of the general formula VI in which A, depending on the reaction conditions used, is a nitro group, an amino group, or a group resulting from the formation of an inter-mediate during the reduction of A--N02 to A=NH2, in which cases the com-of formula VI represent the corresponding azo or hydroazo compounds.
When A is different from NH2, the compounds of the formula VI
are then reduced to compounds of formula III containing an amino group in the 5-position, for instance with an excess of sodium dithionite or with ferrous salts or iron powder or with stannous chloride.

The compounds of formula VI in which Y is oxygen or sulphur and A is a nitro group can also be prepared by reacting the above-mentioned diazonium salt prepared from a compound of formula V (R2=NH2~ with a com-pound of the formula RlYH, in which Rl is as defined above and Y is oxygen or sulphur.

~055948 The starting materials of formula III in which YRl is placed in the 2-position are prepared from the well-~nown 2,4-dihalo-S-nitro-toluenes, the methyl group of which is oxidized to a carboxylic group, whereafter the 2,4-dihalo-5-nitrobenzoic acid in which the halogen atoms may be the same or different is subjected to an Ullmann process as des-cribed above, whereby a compound of the formula IX is obtained:

Ar ~ Hal ~ IX

in which Ar is as defined above and Hal stands for a halogen atom. If desired, esters of the compounds can be used in the reactions, whereby also the compounds of formula IX are obtained as esters. If desired, a saponification can be performed at any step of the preparation of the above and the following compounds. By reacting the compound of formula IX with a compound of the formula RlY'H in wich Y' stands for O, S, or NH, preferably by heating and, if necessary, in the presence of an acid - binding agent, in a suitable solvent or by using the reactant RlY'H as solvent, a compound of the following formula X is obtained:

Ar)3~y'Rl in which Ar, Y' and Rl all are as defined above.
By amination of the compound of formula IX the 2-amino-4-aryl-5-nitrobenzoic acid is formed, which latter compound through a diazotation and following reaction with an appropriate alkene in the manner described above, followed by a throughout hydrogenation yields a compound of the formula III, in which Y stands for alkylene.
In another embodiment the compound of formula IX can be reduced to the corresponding 5-amino derivative, which by following the process described above, can be diazotized, converted to the co~responding lO5S948 5-halosulfonyl derivative which by amidation yields the 5-sulfamyl derivative of the formula XI:

Ar ~ Hal in which Ar and Hal are as defined above. By reacting this compound with the compound RlY'H as described above,-compounds of formula I in which Y stands for O, S, or NH are obtained.
In another embodiment the compounds of formula I in which Y
stands for oxygen, sulphur or methylene and is placed in the 3-position are prepared by reacting a diazonium salt of a compound of formula VII
or an ester thereof Ar ~ VII

ir. which Ar is as defined above, with a compound of the formula ~YH, in which Rl is as defined above and Y stands for oxygen and sulphur, or with an appropriate alkene, in the latter case followed by hydrogenation of the alkene group thus introduced in the 3-position. These reactions are performed in the same manner as already described for the inter-mediates mentioned above.

The starting materials of formula VII are prepared by a Meerwein reaction on a compound of formula V, R2=NH2 and an amidation of the sulfochloride obtained, followed by a reduction of the nitro group to an amino group in known manner.
In another embodiment of the process of an aspect of this invention, the compounds of another aspect of this invention in which Y
stands for O~ S, or NH, can be prepared from the compounds of the formula VIII

105594~

YH
Ar ~ COOH VIII

in which Ar is as defined above by an alkylation. This can be performed either on the free acid or on one of its esters by treatment with a compound RlZ in which Rl has the meaning given above and Z stands for a halogen atom, or an alkyl- or arylsulfonyloxy group, or with a di-~-sulphate, a diazo compound of the formula RlN2, or a quaternary = oniumcompound of the formula RlN (Alk)3, in which Rl has the above meaning and Alk stands for alkyl with from 1 to 6 carbon atoms.
In case of Y standing for NH, the alkylation may also be performed by a reductive alkylation using an aldehyde corresponding to Rl in having the same carbon atom content.

The salts of still another aspect of this invention of the .. .
compounds of an aspect of this invention prepared according to the process of an aspect of this invention are pharmaceutically acceptable salts, and include, for example, alkali metal salts, alkaline earth metal salts, the ammonium salts, or amine salts formed, for instance, from mono-, di- or trialkanolamines or cyclic amines. The esters of yet another aspect of this invention of the compounds of an aspect of this invention are prefe~ably derived from lower aliphatic alcohols, cyanomethanol and benzyl alcohol.
The compounds of an aspect of this invention prepared according to the process of an aspect of this invention are derivatives of biphenyl.
It has unexpectedly been found that these compounds possess an outstan-ding diuretic and saluretic activity with a very low excretion of potassium ions and a low toxicity which make the compounds of an aspect of this invention particularly valuable in human and/or veterinary practice.
The compounds of an aspect of this invention are effective 105594~3 after oral, enteral or parenteral administration, and are preferably prescribed in the form of tablets, pills, dragees, or capsules containing the free acid or salts thereof with atoxic bases, or the esters thereof, mixed with carriers and/or auxiliary agents.
Salts, which are soluble in water, may with advantage be administered by injection. The compounds of an aspect of this invention prepared according to the process of an aspect of this invention are useful in the treat~ent of oedematous conditions, e.g. cardiac, hepatic, renal, lung, and brain oedema, or oedematous conditions during pregnancy, and of pathological conditions which produce an abnormal retension of the electrolytes of the body, and in the treatment of hypertension.
The compounds of an aspect of this invention prepared accor-ding to the process of an aspect of this invention or their salts or esters can be conveniently administered in a dosage unit as a pharmaceu-tical preparation containing from 0.2 mg to 50 mg of the active compound of an aspect of this invention. The compounds of formula I are preferably administered in amounts from 0.5 mg to 10 mg. By the term "dosage unit"
is meant a unitary, i.e. a single dose capable of being administered to a patient, and which may be readily handled and packed, remaining as a physically stable unit dose, comprising either the active material as such or in a mixture of it with a pharmaceutical carrier and auxiliary agents.
In the form of a dosage unit the compounds of an aspect of this invention may be administered one or more times a day at appropriate intervals. The daily dose usually amounts to from 0.5 to 50 mg, always depending, however, on the condition of the patients and according to the prescription of the medical practitioner.
In pharmaceutical compositions containing compounds of an aspect of this invention, organic or inorganic, solid or liquid carriers suitable for oral, enteral, or parenteral administration can be used to make up the composition. Gelatin, lactose, starch, magnesium stearate, talc, vegetable and animal fats and oils, gum, polyalkylene glycol, or other known carriers for medicaments are all suitable as carriers.
In the pharmaceutical compositions, the proportion of thera-peutically active material to carrier substances can vary between 0.5 per cent and 90 per cent.
The compositions may further contain other therapeutic com-pounds applied in the treatment of, for example oedemas and hypertension, besides the well-known auxiliary agents. Such other compounds may be, for instance, Veratrum- or Rauwolfia alkaloids, e.g. reserpine, rescinna~ine or protoveratrine or synthetic hypotensive compounds, e.g.
hydralazine, or other diuretics and saluretics, such as, for example, the well-known benzothiadiazines, e.g. hydroflumethiazide, bendro-flumethiazide, and the like. Potassium-sparing diuretics, e.g. triam-terene, may also be us~d in the preparation of the compositions. For some purposes it may be desirable to add small amounts of aldosterone antagonists, e.g. spironolactone.
The invention in its various aspects will now be illustrated by the following non-limiting Examples, from which the details of - various embodiments will be apparent.

EX~r~LE 1.
3-~enzylamino-4-phenyl-4-sulfan~Lbenzoic acid.
A. ~S~th } nitro-4-phenylbenzoate.
A mixture of methyl 4-chloro-3,5-dinitrQbenzoate (60 g), iodoben-zene (36 ml~ and copper powder (60 g) iB stirred at 145-155C for 4-5 hours.
After oooling, the resulting solids are extracted with three portion~ of boil-ing chloroform (each portion 150 ml), and the cambined extracts are, after filtration, evaporated in vacuo. After trituration of the residue with methanol (150 ml) foll~ff3d by recrystallization from 2-methoxyethanol, methyl 3,5-dinitro-4-phenyIbenzoate is obtained with a melting point of 147.5-148C.

B. 3,5- ~ Ibenzoic acid.
To a stirred suspension of methyl 3,5-dinitro-4-phenylkenzoate (145 g) in 2~methoxyethanol (1.5 1), 2N ~odium hydroxide (300 ml) is added droF~Jise during about 30 minutes. After additional stirring for about 15 minutes, the resulting solution is acidified by the dropwise addition of

4 N hydrochloric acid (250 ml), and the mixture is thereafter d;luted with wat~r (about 3 1). ~fter aooling, the resulting preci~itate i~ oollected by filtration, washed with water and dried. After recrystallization from aqueous ethanol, 3,5-dinitro-4-phenylbenzoic acid is obtained with a m~ltin~
point of 219-221C.

.

- 14 - ~

1~55948 C. 3-Amino-5-nitro-4-phenylbenzoic acid.
Tb a stirred solution of 3,5-dinitro-4-phenylbenzoic acid (135 g) in a mizture of pyridine (625 ml) and water (625 ml), sodium dithionite (235 g) is added in portions during about 30 minutes, keeping the temperature at 12-15C by external ooolinq. After additional ~tirring at this tenpera-ture for about 15 minutes, the resulting solution is acidified by the addi-tion of cone, hydrochloric acid (750 ml), keeping the temperature below 25C
by the addition of ice to the reaction mlxture. The mixture is left fo~
hnut 20 hours, and the resulting precipitate is then colle_ted by filtration, washed with water and dried, After recrystallization from aqueous ethanol, 3-amino-5-nitro-4-p~enylbenzoic acid is obtained with a mElting point of 247-249C (dec.).

D. 3-~enzylamino,5-nitro-4-pbenyLbenzoic acid.
A mixture of 3-amin~-S-nitro-4-phenylben3oic acid (4.0 g), benzyl-bronide ~4.0 ml), and ethanol ~40 ml) is refluxed for 40 hour~. After 16 and 24 hours additional amounts of benzylbromide ~each portion 2.0 ml) are added. After cooling, the mixture is evaporated m vacuo and the obtained crude ethyl 3-benzylamino-5-nitro-4-ph~nylbenzoate is saponified by heating with a mLxture of 2 N ~odium hydroxide (25 ml) and ethanDl (25 ml) for a~out 1 hour. The cooled mixture i~ acidified with acetic acid (5 ml) and diluted with water ~15 ml). After cooling lQ~S~48 at a~out 5C for 48 hours, the regultin~ precipitate is colle~ted by filtra-tion, washed with water and dried. After recrystallization from aqueous ethanol, 3-benzylamuno-5-nitro-4-phenylbenzoic acid is obtained with a melting point of 188-189C.

E. 5-Amino-3-benzylanuno-4-phenylbenzoic acid.
Tb a stirred solution of 3-benzylamlno-5-nitro-4-phenylbenzoic acid (3.0 g) in a mixture of pyridine ~15 ml) and water ~15 ml), sodium dithionite ~6.0 g) is added in portions during about 15 minutes. me mixture is heated on a stea~ bath for about 30 minutes, and is then evaporated in vacuo. The residue is treated with cold 1 N acetic acid (about 50 nL) and after cobling, the resulting precipitate is collected by filtration, washed with water and dried. After recrystallization twice from aqueous ethanol, 5-amino-3-benzylamunc-4-phenylbenzoic acid is obtained with a melting point of 179-181C.

F. 3-BenzylamunL-5-chlorosulfonyl-4-phenylbenzoic acid .

A solution of 5-amino-3-benzylamino-4-phRnylbenz~ic acid (0.65 g) and potassium nitrite (0.17 g) in 0.5 N potassium hydroxide (8 nl) is drop-wise added to a mixture of acetic acid (7 nl) and oonc. hydrochloric acid (7 ml), while stirring at 0C. After additional tirring at this , lOSS948 temperature for about 10 minuteg, the resulting diazonium olution is added to a mixture of acetic acid ~7 ml) saturated with S02 and cupric chloride dihydrate (0.2 g) in water (o.6 ml). After additional stirring for 2-3 hours, the precipitate~ 3-benzylamino-5-chlorosulfonyl-4-phenylbenzoic acid is o~l-lected by filtration, washed with ~Yater and dried.

G. 3-Benzylamino-4-phenyl-5-s~lfamylbenzoic acid.
3-~enzylsmino-5-chlorosulfonyl-4-~henylbenzoic acid (1.0 g) is in portions added to conc. ammDnium hydroxide ~10 ml) while stirring at 10-12C.
After additional stirring at room temperature for abnut 18 hours, the result-ing solution is dropwise added to an excess of icecold 4 N hydrochloric acid.
The resulting precipitate is collecte~ by filtration, ~sh3d with water and dried. After recrystallization from aqueous ethanol, 3-benzyl-amino-4-phenyl-

5-sulfamylben2oic acid is obtained with a melting point of 221-222C.

EX~MoeLE 2.
3-Benzyloxy-4-phenyl-5-sulfamylbenzoic acid.
A. 5 ~ -nltro-2-ph~nyLbenzenediazon um tetrafluoroborate.
A hot solution of 3-amino-5-nitro-4-phenyLbenzoic acid (39 g;
prepared as in ExamFle l, step C~ and potassium nitrite ~15 g) in 1 N
potassium hydroxide (260 ml) is .': .' ~' "

,, , -. .' - - ' ~

10555~48 sdded dropwise to a mixture of acetic acid (150 ml) and conc. hydrochloric acid (150 ml), while stirring vigorously at -2 to 2C. After additional stirring at this temperature for about 10 minutes, 50% hydrofluoroboric acid (100 ml) is added during about 5 minutes, keeping the temperature belcw 5C

by external oooling. After additional stirring at about -10C for 1 hDur, the precipitated 5-carboxy-3-nitro-2-phenylbenzenediazonium tetraflu~roborate is oollected by filtration, washed with icecold ~ater (tw~ portions of each 25 ml) and dried.

B. 3-Hydroxy-5-nitro-4-phenyLbenzoic acid.
5-Carb~xy-3-nitro-2-phenylbenzenediazonium tetrafluoroborate (llO-g) is added in portions to a stirred and refLuxing nixture of acetic anhydride (275 ml) and acetic acid (275 ml). m e mixture is refluxed for a further 4-5 hours and is then poured into ice-water (about 4 liters). The mixture is left for 20 hours, and the precipitated crude 3-acetoxy-5-nitro-4-phenyl-benzoic acid is collected by filtration, washed with water and-dried. It is saponified by heating with 4 N sodium hydroxide ~250 ml) for 30 minutes; the resulting solution i8 left at 5C for about 20 hours and is then filtered.

The filtratate is acidified with 4 N hydrochloric acid to precipitate 3-hydroxy-5-nitro-4-phenylbenzoic acid. It is collected by filtration, ~ashed with water and dried. After recrystallization fram aqueous methanol, the acid is obtained with a nElting point of 213-215C.

10555~48 C. 3-Eenzyloxy-5-nitro-4-phenylbenzoic acid.
A mixture of 3-hydroxy-5-nitro-4-phenylbenzoic acid (3.0 g), benzylbromide (1.5 ml) and lN sodium hydroxide ~30 ml) is stirred at room temperature for 6-7 hours. After oooling, the precipitated sodium 3-benzyl-oxy-5-nitro-4-phenyIbenzoate is collected by filtration and washed with a small amount of iceoold water. After drying, the sodium salt is dissolved in hot wat~r (100 ml), and the 3-benzyloxy-5-nitro-4-phenyLbEnzoic acid is precipitated by addition of 4 N hydrochloric acid (10 ml). After oooling, the acid is collecte by filtration, washed with water and dried. After re-crystallization t~lice from isopropanol, it is obtained with a melting point of 188.5-.89.5C.

D. _-Amino-3-benzylo~y-4-phenylbenzoic acid.
T~ a solution of 3-benzyloxy-5-nitro-4-phenylbenzoic acid (2.5 g) in a mixture of pyridine (8 ml) and w~ter (16 ml), sodium dithionite (5.0 g) i9 added in portions during about 15 minutes. he ~ixture is heated on a steam bath for 30 minutes, and is then cooled in an ice-bath. m e stirred and oooled mixture i9 then aoidified with 4 N hydrochloric acid to precipi-tate 5-aminL-3-benzylo~y-4-phenyIbenzoic acid. The acid is collected by filtration, washed with water and dried. After recrystallization from aqueous ethanol, it i9 obkain3d as a hemihydrate with a melting point of 161-162C.

lOSS94~

E. 3-Benzyloxy-5-chlorosulfonyl-4-phenylbenzoic acid., By replacing in Example 1, step F, 5-amino-3-ben~ylamino-4-phenyLbenzoic acid with an equLmolar amount of 5-amino-3-benzyloxy-4-p~enyl-benzoic acid, and following the procedure described, 3-benzyloxy-5-chloro-sulfonyl-4-phenylbenzoic acid is obtained.

F. 3-Benzyloxy-4-phenyl-5-sulfamylbenzoic acid.
3-BenzylQxy-5-chlorosulfonyl-4-phenylbenzoic acid (1.0 g) is in portions added to conc. ammonium hydroxide (10 ml), while stirring at 10-12C. After additional stirring at roam temperature for 18-20 hours, the mixture is left in a refrigerator for 2-3 hours. m e separated ammonium salt is collected by filtration and washed with a sm211 amount of icecold water. After drying, the salt is dissolved in 1 N sodium hydroxide (10 ml) and the 3-benzyloxy-4-phenyl-5-~ulfamyIbenzoic acid is precipitated by the dropwise additiQn of the ~olution to 1 N hydrochloric acid (12 ml). The acid i~ collected by filtration, washed with water and dried. After re-crystallizati~n from aqueD~o ethanol, it is obtained with a melting point of 199-200C.

EXAMP$E 3 3-Eth~xy-4-phenyl-5-sulfamyIbenzoic acid.
A. Ethyl 3-hydroxy-5-nitro-4- ~ ylbe`nzoate.
A mixture of 3-hydroxy-5-nitro-4-phenylbenzoic acid (22 g; pre-pared as in Example 2, step B), oanc. sulfuric 105594~

acid (10 ml) and ethanol (400 ml) is refluxed for 20 hours. The resulting solution is concentrated in vacuo to a~out 100 ml and is then diluted with water (about 300 ml). m e separated ethyl 3-hydroxy-5-nitro-4-pbenylbenzoate i9 collected by filtration, washed with water and dried. After recrystal-lization from carbon tetrachloride, the ester is obtained with a melting point of 128-130C.

. 3-Ethoxy-5-nitro-4-phenylbenzoic acid.
To a solution of sodium ethanolate (prepared from 0.5 g of sodium) in dry ethanol (40 ml~, ethyl 3-hydroxy-5-nitro-4-phenyLbenzoate (4.4 g) is added followed by ethyl iodide (2.5 ml), and the resulting solution is re-fluxed for 20 hours. After about 6 hours an additional am~unt of sodium ethanolate (prepared from 0.25 g of sodium) in dry ethanDl (lQ ml) is added followed by ethyl iodide (1.3 ml). The mixture is evaporated in vacuD, 2 ~
sodium hydroxide (25 ml) is added to the residue, and the mixture is heated on a steam bath for 30 minutes to form a clear solution. On cooling, sodium 3-ethoxy-5-nitro-4-phenyLbenzoate separates. It is collected by filtration, and ~ashed with a small am~unt of icecold water. After drying, the sodium salt is~dissolved in h~t ~later (50 ml), and the 3-ethoxy-5-nitro-4-phenyl-benzoic acid is pre-lO5S5~48 cipitated by addition of 4 N hydl~chloric acid (5 ml). Afte~ c~oling, the acid is collected by filtration, washed with water and dried. After re-crystallization fnom aqueous ethanol, it is obtained with a melting point of 174-176C.

C. 5-Amino-3-et ~ -4- penylbenzoic acid.
By replacing in Exlmple 2, ~tep D, 3-benzyloxy-5-nitro-4-phenyl-benzoic acid with 3-ethQxy-5-nitro-4-phenylbenzoic acid, and foll~ing the procedure described, 5-amuno-3-ethoxy-4-phenyLbenzoic acid is obtained with a melting point of 137.5-138.5C.

D. 5-Chlorosulfonyl-3-ethoxy-4-phenylbenzoic acid.
Ey replacing in Example 1, step F, 5-awlno-3-benzylanuno-4-phenyl-benzoic acid with an equimolar amount of 5-amms-3-ethQxy-4-phenyLbenzoic acid, and following the procedure described, 5-chlorosulfonyl-3-ethoxy-4-phen~Lbenzoic acid is obtained.

E. _Ethoxy-4-pheny-l-5-su-lfa~ylbenzoic acid.
. By replacing in Exawple 2, step F, 3-benzyloxy-5-chlorosulfonyl-4-phenylbenzoic acid with 5-chlorosulfonyl-3-ethDxy-4-phenylbenzoic acid, and follcwing the procedure described, 3-etho~y-4- penyl-5-sulfamylbenzoic acid is obtained with a melting point of 149-150C.

1()5~ 48 E~U~LE 4 4-Phenyl-3-n-pro~y-5-sulfamylbenzoic acid.
A. 5-Nitro-4-phenyl-3-n-prop~ybenzoic acid.
By replacing in Example 3, step B, ethyl iodide with an equLmDlar a~ount of n-propyl iodide, and following the procedure described, 5-nitro-4-phenyl-3-n-propo~y-benzoic acid i9 obtained with a melting point of 142.5-144C.

B. 5~Amino-4-phenyl-3-n-propo~ybenzoic acid.
By replacing in Example 2, step D, 3-benzyloxy-5-nitro-4-phenyl-benzoic acid with 5-nitro-4-phenyl-3-n-propoxybeizoic acid, and following the prooedure described, 5-amino-4-phenyl-3-n-propo~ybenzoic acid is obtained with a melting point of 101-102C.

C. 5-~hlorDsulfonyl-4-phRnyl-3-n-propoxybenzoic acid.
By replacing in Example 1, step F, 5-amlno-3-benzylamuno,4-phenyl-benzoic acid with an equimDlar amDunt of 5-amlnL-4-phenyl-3-n-propoxybenzoic acid, and following the prooedure descrikQ~, 5-chlorosulfonyl-4-phenyl-3-n-propoxybenzoic acid is obtained.

D. 4-Phenyl-3-n-propoxy-5-sulfam~lbenzoic acid.
Ey replacing in Example l, step G, 3-benzylamino-5-chlorDsulfonyl-4-phenyIben2oic acid with 5-chlorosulfonyl-4-phenyl-3-n-propoxybenzDic acid, and following the procedure descriho~ 4-phenyl-3-n-propoxy-5-sulfam~lbenzoic acid is obtained with a melting point of 155-157C.

105594~3 E~LE 5.
3-n-Butoxy-4-phe yl-5-sulfamylbenzoic acid.
A. 3-n-Butoxy-5-n-i-tro-4-phenylbenzoic acid.
By replacing in Example 3, step B, ethyl iodide with an equLmolar amount of n-butyl icdide, and follcwing the procedure descr;hQ~, 3-n-butoxy-S-nitro-4-phenyIbenzoic acid is obtained with a melting point of 133-134C.

B. 5-Amino-3-n-butoxy-4-phenylbenzoic acid.
By replacing in Example 2, step D, 3-benzyloxy-5-nitro-4-phenyl-benzoic acid with 3-n-butoxy-5-nitro-4-phenyLbenzoic acid, and follcwing the procedure described, 5-amuno,3-n-butoxy-4-phenylbenzoic acid is obtained with a melting point of 122-124C.

C. 3-n-Butoxy-5-chlorosulfonyl-4-phenylbenzoic acid.
By replacing in ~xample 1, step F, 5-amino-3-benzylamino-4-phenyl-! benzoic acid with an equimolar amount of 5-amino-3-n-butoxy-4-phenylbenzoic acid, and following the proclrure described, 3-n-butoxy-5-chlorosulfonyl-4-phenylbenzoic acid is obtained.

D. 3-n-Butoxy-4- ~enyl-5-sulfamylbenzoic acid.
By replacing in Example 1, step G, 3-benzylamunL-5-chlorosulfonyl-4-phenylbenzoic acid with 3-n-butoxy-5-chlorosulfonyl~4-phenylbenzoic acid, and follcwing the procedure described, 3-n-butoxy-4-phenyl-5-sulfamylbenzoic acid is obtained crystallizing with 0.25 mole of water with a meltin~ point of 129-131C.

10555~4!3 E~U~PLE 6.
3-n-P ~ yl-5-sulfamyLbenzoic acid.
A. 5-Nitro-3-n-pentylox~-4-phenylbenzoic acid.
By replacin~ in Example 3, step B, ethyl iodide with an equLmolar amount of n-pentyl iodide, and follcwing the procedure de6cribed, 5-nitro-3-n-pentyloxy-4-phenylbenzoic acid is obtained with a melting point of 144-146C.

B. 5-Amino-3-n-pentyloxy-4-phenylbenzoic acid.
By replacing in Example 2, step D, 3-benzyloxy-5-nitro-4-phenyl-b~nzoic acid with 5-nitro-3-n-pentyloxy-4-phenylbenzoic acid, and following the procedure described; 5-amino-3-n-pentyloxy-4-phenylbenzoic acid is ob-tained crystallizing with 0.25 mole of ~7ater with a melting point of 134-135C.

C. 5-Chlorosulfonyl-3-n-pentyloxy-4-phenyIb3nzoic acid.
By replacing in Example 1, step F, 5-amuno-3-benzylaminL-4-phenyl-benzoic acid with an equLmolar amount of 5-amLno-3-n-pentyloxy-4-phenylbenzoic acid, and following the procedure described, 5-chlorosulfonyl-3-n-pentyloxy-4-phenylbenzoic acid is bbtained.

D. 3-n-PentyloYy-4- ~ yl-5-æulfam~lbenzoic acid.
By replacing in Example 2, step F, 3-benzyloxy-5-chloroæulfonyl-4-phenylbenzoic acid ~7ith 5-chlorosulfonyl-3-n-pentyloxy-4-phenyLbenzoic acid, and following the procedure descriked, 3-n-pentyloxy-4-phenyl-5-sul-fam~lbenzoic acid i8 Qbtained with a melting point of 152 155C.

EXAMPLE 7.
4-Phenyl-3-~opargylo~y-s-gulfamylbenzoic acid.
A. 5-Nitro-4-phenyl-3-propargyloxybenzoic acid.
By replacing in Example 3, step B, ethyl iodide ~ith an eouimDlar amDunt of propargyl bronide, and following the procedure described, 5-nitro-4-phenyl-3-propargyloxyhenzoic acid is obtained with a melting point of 145-147C.

B. 5-Amlno~4-phenyl-3-propargyloxybenzoic acid.
By replacing in Example 2, step D, 3-benzyloxy-5-nitro-4-phenyl-benzoic acid with 5-nitro-4-phenyl-3-propargyloxybenzoic ~cid, and following the procedure described, 5-amino~4-phenyl-3-propargyloxybenzoic acid is ob-tained with a melt mg point of 172-173C.

C. 5-Chlorosulfonyl-4-phenyll3-propargylo~ybenzoic acid.
By replacing in Example 1, step F, 5-a~Ino-3-benzylamino-4-phenyl-benzoic acid with an equimolar amDunt of 5-amuno-4-phenyl-3-propargyloxy-benzoic acid, and following the procedure described, 5-chlorosulfonyl-4-phenyl-3-propargyloxybenzoic acid is obtained.

D. 4-Phenyl-3-proparlyloxy-5-sulfamylbenzoic acid.
By replacing in Example 1, step G, 3-benzylamino-5-chlorosulfonyl-4-phenyLbenzoic acid with 5-chloro~ulfonyl-4-phenyl-3-propargyloxybenzoic acid, and followLng tho p~ocedure des¢ribed, 4-pbenyl-3-propargyloxy-5-sul-famyLbenzoic acid is obt~ined with a melting point of 154-155C.

105Sg4~
EX4`~LE 8.
3-t2-phenethoxy)-4-phenyl-5-sulfamylbenzoic acid.
A. 5-nitro~3-(2-phenethoxy)-4-phenylbenzoic acid.
By replacing in Example 3, step B, ethyl iodide with an equimolar amount of 2-phenylethyLbromide, and following the procedure described, 5-nitro-3-(2-phenethoxy)-4-phenyLbenzoic acid is obtained with a melting point of 172-173C.

B. 5-Amino-3-(2-phenethoxy)-4-phenylbenzoic acid.
By replacing in Example 2, step D, 3-benzyloxy-5-nitro-4-phenyl-benzoic acid with 5-nitro-3-(2-phenethoxy)-4-phenyLbenzoic acid, and follow-ing the procedure described, 5-anuno-3-(2-phenethoxy)-4-phenyibenzoic acid i5 obtained with a melting point of 159-160C.

C. 5-Chlorosulfonyl-3-(2-phenethoxy)-4-phenyLbenzoic acid.
! By replacing in Example 1, step ~, 5-amm o,3-benzylamuncr4-phenyl-benzoic acid with an equimolar amount of 5-amino-3-(2-~enethoxy)-4-phenyl-benzoic acid and following the procedure described, 5-chlorosulfonyl-3-(2-phenethoxy)-4-phenyLbenzoic acid is obtained.

D. 3-(2-Phenethoxy)-4-phenyl-5-~ulfa~ylbenzoic acid.
By réplacing in Example 2, step F, 3-benzyloxy-5-chlorosulfonyl-4-phenylbenzoic acid with 5-chlorosulfonyl-3-(2-pbenethoxy)-4-phenyLbenzoic acid and following the prnc~dure described, 3-(2-phenethoxy)-4-phenyl-5-sulfamyLbenzoic acid i~ bbtained, cry~tallizing with 0.25 mole of water with a melting point of 108-110C.

1055g~

EU~D?LE 9 4-Phenyl-5-sulfamyl-3-(3-thenyloxy)benzoic acid.
A. 5-Nitro-4-phenyl-3-~3-thenyloxy)benzoic acid.
By replacing in Example 3, step B, ethyl iodide with an equimDlar amount of 3-bromamethylthiophene, and follcwLng the procedure described, 5-nitro-4-phenyl-3-(3-thenyloxy)benzoic acid is obtained with a mElting point of 184-186C.

B. 5-Amino-4-~henyl-3-(3-thenyloxy)benzoic acid.
By replacing in Example 2, step D, 3-benzyloxy-5-nitro-4-phenyl-benzoic acid with 5-nitro-4-phenyl-3-(3-thenyloxytbenzoic acid, and follc~ing the procedure described, 5-amino-4-phenyl-3-(3-thenyloxy)benzoic acid is obtained as a hemLhydrate with a melting point of 139-140C.

C. 5-Chlorosulfonyl-4-pihenyl-3-~3-thenyloxY~benzoic ac~.
? By replacing in Example 1, step F, 5-amino-3-benzylaminc-4-pihenylbenzoic acid with an equLmolar amount of 5-anino-4-phenyl-3-(3-thenyloxy)benzoic acid, and fbllcwing the procedure described, 5-chlorosul-- fonyl-4-phenyl-3-(3-thenyloxy)benzoic acid is obtained.

D. 4-Phen~1-5-sulfamyl-3-~3-thenyloxy)benzoic acid.
By replacing in Example 1, step G, 3-benzYlamnno-S-1(~5S948 chlorosulfonyl-4-phenyLbenzoic acid with 5-chlorosulfonyl-4-phenyl-3-(3-thenyloxy)benzoic acid, and following the procedure descr~h~ 4-phenyl-S-sulfamyl-3-(3-thenyloxy)benzoic acid is obtained with a melting point of 222-223C.

- EX~MPLE 10 3-Benzylthio-4-phenyl-5-sulfamylbenzoic acid.
A. Ethylxanthic acid 5-carboxy-3-nitro-2-phenylphenyl ester.
S-C~rtDxy-3-nitro~2-phenylbenzenediazonium tetrafluoroborate (75 g;
prepared as in Exam~le 2, step A) is added in portions to a solution of po-tassium ethyl xanthate (24 g) in water (250 ml), while stirring at 65-70C.
After additional stirring at this te~perature for 30 minutes, the mixture is cooled, and 4 ~ hydrochloric acid (25 ml) is added follcwed by ~later (200 ml). The separated ethylxanthic acid 5-carboxy-3-nitro-2-phenyl-phenyl ester is collected by filtration, washed ~Jith water and dried.

B. 3-Benzylthio-5-nitro-4-phenylbenzoic acid.
A mixture of eth~lxanthic acid 5-carboxy-3-nitro-2-phenylphenyl ester (3.7 g) and 2 ~ sodium hydroxide (35 ml) is heated on a steam bath for 10 minutes, while nitrcgen i9 bubled through the muxture. After cooling to . .

1~)5S~4~3 40C, benzyl bromide (2.0 ml) is added to the resulting solution, and the mixture is stirred for 4-5 hours in a nitrogen atmosphere. After cooling, the separated sodium 3-benzylthio-5-nitro-4-phenylbenzoate is collected by filtration, washed with a gmall amDunt of icecold water and dried. The sodium salt i8 dissolved in hot ~ater, and the 3-benzylthio-5-nitro-4-phenyl-benzoic acid is precipitated by acidification with 4 ~1 hydrochloric acid (5 ml). After cooling, the acid is col3ected by filtration, ~7ashed with water and dried. After recrystallization from aqueous ethanol, it is ob~
tained with a melting point of 188-189C.

C. 5-AminL-3-benz~lthio-4-phenyLbenzoic acid.
By replacing in Example 2, step D, 3-benzyloxy-5-nitro-4-phenyl-benzoic acid with 3-benzylthio-5-nitro-4-phenylbenzoic acid, and following the procedure described, 5-anino-3-benzylthio-4-phenyLkenzoic acid is ob-tained with a ~elting point of 173-174C.

!

D. 3-~enz~x~thic-5-chloro~ulfonyl-4-phenylbenzoic acid.
By replacing in ~xample 1, step F, 5-amino-3-benzylamino-4-phenyLbenzoic acid with an equLmol æ amDunt of 5-amLno-3-benzylthio-4-phenyl-benzoic acid and following the procedure described, 3-benzylthio-5-chloro-sulfonyl-4-phenyLbenzoic acid is obtained.

, 1055941~

E. 3-Eenzylthio- ~ sulfamylbenzoic acld.
By replacing in Example 2, step F, 3-benzyloxy-5-chlorosulfonyl-4-phenylbenzoic acid with 3-benzylthio-5-chlorosulfonyl-4-phenyLbenzoic acid, and follcwing the procedure described, 3-benzylthio-4-phenyl-5-~ulfamylbenzoic acid i~ obtained as a hemihy*rate with a melting point of 114-120C.

EXP~qPIE 11 4-Phenyl-3-n-pro~lthio-5-sulfamylbenzoic acid.
A. 5-Nitro-4-~n~1-3-n-propylthiobenzoic acid.
By replacing in Example 10, step B, benzyl bromide with an equi-molar amount of n-propyl iodide, and following the procedure described, 5-nitro-4-phenyl-3-n-propylthiobenzoic acid is obtained with a melting point of 178.5-180JC.

B. 5-Amino-4-phenyl-3-n-propylthiobenzoic acid.
By replacing in EXample 2, step D, 3-~enzyloxy-5-nitro-4-phenyl-benzoic acid with 5-nitro-4-phenyi-3-n-propylthioben2oic acid, and follc~ing the procedure described, 5-andnc-4-phenyl-3-n-propylthiobenzoic acid is ob-tained~with a melting point of 190-191C.

~)5~48 C. 5-Chloro~ulfonyl-4-phenyl-3-n-pro~ylthiabenzoic acid.
By replacing in EXimple 1, step F, 5-amino-3-benzylamino-4-phenyl-benzoic acid with an equImolar amount of 5-amuno-4-phenyl-3-n-propylthio-benzoic acid, and foll~ing the procedure de-qcribed, 5-chlorosulfonyl-4-phenyl-3-n-propylthiobenzoic acid i.s abtain~d.

D. 4-Phenyl-3-n-pro~lthio-5-sulfamylbenzoic acid.
By replacing in EXample 1, step G, 3-benzylamino-5-chlorosulfonyl-4-phenylbenzoic acid with 5-chlorosulfonyl-4-phenyl-3-n-propylthiobenzoic acid and following the procedure described, 4-phenyl-3-n-propylthio-5-sul-fa~yLbenzoic acid is obtained as a hydrate with a melting point of 85-87C.

3-n-Butylthio-4-phenyl-5-su~ yLberz-oic acid.
A. 3 ~ 1benzoic acid.
t By repLacing in Example 10, step B, benzyl bromide with an equi-molar amount of n-butyl iodide, and follcwing the procedure described, 3-n-butylthio-5-nitro-4-phenylbenzoic acid is abtained crystallizing with 0.67 mDle of water with a melting point of 147-148C.

lO5S~ 4~
B. -Amino-3-n-butylthio-4-phenyIbenzoic acid.
By replacing in Example 2, step D, 3-benzyloxy-5-nitro-4-phenyl-benzoic acid with 3-n-butylt~io-5-nitro-4-phenylbenzoic acid, and following the prooedure described, 5-amuno,3-n-butylthio-4-phenylbenzoic acid i~ ob-tained with a nelting point of 143-144C.

C. 3-n-Butylthio-5-chlorosulfonyl-4-phenylbenzoic acid.
By replacing in Example 1, step F, 5-amino-3-benzylamino-4-phenyIbenzoic acid with an equimolar amount of 5-amino-3-n-butylthio-4-p,henylker~oic acid, and following the procedure described, 3-n-butylthio-5-chlorosulfonyl-4-phenylbenzoic acid is obtained.

. 3-n-Butylthio-4-~henyl-5-sulfamyLbenzoic acid.
By replacing in Example 1, s~ep G, 3-benzylamino-5-chlorosulfonyl-4-Fhenylbenzoic acid with 3-n-butylthio-5-chlorosulforyl-4-phenvIbenzoic acid, and following the procedure described, 3-n-butylthio-4-phenyl-5-sulfamyl-benzoic acid is obtained as a hydrate with a melting point of 75-77C.

EX~æLE 13.
3-Isopentylthio-4-phenyl-5-sulfamvLbenzoic acid.
. 3-Is ~ trn-4-~henylbenzoic acid.
By replacing in Example 10, step B, benzyl b mmide with an equimDlar amDunt of isopentyl iodide, and follcwing the procedure described, 3-iso-pentylthio-5-nitro-4-phenylbenzoic acid is obtained with a melting point of 143-144C.

.- ., - , .

1~)5~9~

B. 5-Aminor3-iso~3ntylthlo-4-phenyLbenzoic acid.
Ey replacing in Example 2, step D, 3-benzyloxy-5-nitro-4-phenyl-benzoic acid with 3-isopentylthio-S-nitro-4-phenyLbenzoic acid, and foll~l-ing the procedure described, 5-amuno-3-isopentylthio-4-phenylbenzoic acid i5 obtained crystalli~ing with 0.25 mole of ~4ater with a melting point of 124.5-12~.~C.

C. 5-Chlorosulfonyl-3-isopentylthio-4-phenyLbenzoic acid.
By replacing in Example 1, step F, 5-aminc-3-benzylamuno-4-phenyIbenzoic acid with an equimolar amDunt of 5-amino-3-isopentylthio-4-phenyLbenzoic acid, and foll~4ing the prooedure described, 5-chlorosulfonyl-3-isopentylthio-4-phenylbenzoic acid is obtained.

D. 3-Isopentylthio-4-phenyl-5-sulfamyLbenzoic acid.
~ y replacing in Example l, step G, 3-benzylamino-5-chlorosulfon~l-4-phenyLbenzoic acid with 5-chlorosulfonyl-3-isopen~ylthio-4-phenyLbenzoic acid, and following the procedure described, 3-isopentylthio-4-phenyl-5-sulfamylbenzoic acid is bbtained crystallizing with 0.5 mole of ethanol with a melting point of 70-74C.

EX~LE 14 3-Allylthio-4-phenyl-5-sulfamyLbenzoic acid.
A. 3-Allylthio-5-nitro-4-phenyIbenzoic acid.
By replacin~ in Ex3mple 10, step B, benzyl bromide ~ith an equi-molar amount of allyl bromide, and following the lQ5594~3 procedure described, 3-allylthio-5-nitro-4-phenyLbenzoic acid is obtained with a melting point of 152-153.5C.

B. 3-Allylthio-5-anino~4-phenylbenzoic acid.
By replacing in Example 2, step D, 3-benzyloxy-5-nitro~4-phenyl-benzoic acid with 3-allylthio-5-nitro-4-phenylbenzoic acid, and following the procedure described, 3-allylthio-5-amuno-4-phenyLbenzoic acid is obtained with a melting point of 149.5-150.5C.

C. 3-Allylthio-5-chlorosulfonyl-4-phenylben2oic ac~d.
By replacing in Example 1, step ~, 5-amino-3-benzylamino-4-phenylbenzoic acid with an equLmolar amount of 3-allylthio-5-aminL-4-phenyl-benzoic acid, and following the procedure described, 3-allylthio-5-chloro-sulfonyl-4-plhenylbenzoic acid is obtained.

D. 3-Allylthio-4-p~Rnyl-5-sulfamyLbenzoic acid.
By replacing in Example 1, step G, 3-benzylamuno-5-chlorosulfonyl-4-phenylbenzoic acid with 3-allylthio-5-chlorosulfonyl-4-phenylben~oic acid, and fol-lowing the ~rooedure descr;hed, 3-allylthio-4-phenyl-5-sulfamyl-benzoic acid is obtained as a hydrate with a mElting point of 78-81C.

, EX~MPLE 15 3-Crotylthio-4-phenyl-5-sulfamylbenzoic acid.

A. 3-Crotylt~ ~ ylbenzoic acid.

By replacing in Example 10, step B, benzyl brcmide l~SC948 with an e~uimDlar amount of crotyl bro~ide, and following th~ procedure described, 3-crotylthio-5-nitro-4-phenylbenzoic acid is obtained with a ~elt-ing point of 138.5-140C.

. 5-Amino_3-crotylthio-4-phenylbenzoic acid.
By replacing in Example 2, step D, 3-benzyloxy-5-nitro-4-phenyl-benzoic acid with 3-crotylthio-5-nitro-4-phenylbenzoic acid, and follo~ling the procedure described, 5-amLno-3-cro~ylthio-4-phenylbenzoic acid i5 ob-tained with a melting point of 102-104C.

C. 5-Chlorosulfonyl-3-crotylthio-4-phenyLbenzoic acid.
By replacing in Example 1, step F, 5_amLno-3-benzylanuno-4-phenyl-benzoic acid with an e~uimolar amount of 5-amuno-3-crotylthio-4-phenylbenzoic acid, and following the procedure described, 5-chlorosulfonyl-3-cm tylthio-4 phenylbenzoic acid is obtained.

!
D. 3-Crotylthio-4 ~ -5-sulfa~Ibenzoic acid.
By replacing in Example 1, step G, 3-benzylanuno-5-chlom sulfonyl-4-phenyLbenzoic acid with 5-chlom sulfonyl-3-crotylthio-4-phenyIbenzoic acid, and following the procedure deecribed, 3-c m tylthio-4-phenyl-5-sulfamyl-benzoic acid is obtained crystallizing with 0.5 mole of ethanol with a melt-ing point of 89-91C.

~, ~

15~55~48 EXA~PLE 16 4-Phenyl-5-sulfamyl-3-(3-thenylthio)benzoic acid.
A. 5-~itroh4~phenyl-3-(3-thenylthio)benzoic acid.
By replacing in Example 10, step B, benzyl bro~ide with an equi-m~lar a~ount of 3-bromo~ethylthiophene, and follc~7ing the procedure descr;hc~, 5-nitro-4-phenyl-3-(3-thenylthio)benzoic acid is obtained crystallizing ~ith 0.25 mDle of ~ater with a,~elting point of 159-161C.

B. 5-Amino-4-phenyl-3-(3-thenylthio)benzoic acid.
By replacing in Example 2, step D, 3-benzyloxy-5-nitro-4-phenyl-benzoic acid with 5-nitro-4-phenyl-3-(3-thenylthio)benzoic acid, and folJow-ing the procedure described, 5-amino-4-phenyl-3-(3-thenylthio)7aenzoic acid is obtained with a melting point of 142-145C. (dec.).

C. 5-Chlorosulfonyl-4-p~enyl-3-(3-thenylthio)benzoic acid.
By replacing in Example 1, step F, 5-amm o-3-benzylanuno-4-phenyl-benzoic acid with an equimDlar amount of 5-amino-4-phenyl-3-(3-t~enylthio)-benzoic acid, and follc~7ing the procedure descrihi~, 5-chlorosulfonyl-4-phenyl~3-(3-thenylthio)benzoic acid i~ obtained.

D. 4-Phenyl-5-sulfa~y1-3-(3-thenylthio)benzoic acid.
By replacing in Example 2, step ~, 3-benzyloKy-5-chlorosll-fonyl-4-phenyLbenzoic acid with 5-chlorosulfonyl-4-phenyl-3-~3-t~enylthio)benzoic acid, and followin~ the F~ocedure described, 4-phenyl-5-sulfamyl-3-(3-thenyl-thio)benzoic acid is obt~ined as a hydrate with a melting point of-92-94C.

~(~S~ 8 EXAMPL~ 17 4-Phenyl-3-(2~~ridylmethylthio?-5-sulfamyLbenzoic acid A. 5-Nitro-4-~henyl~3~(2~pyridylmethylthio)benzoic acid By replacing in Example 10, step B, benzyl bromide with an equi-molar amount of 2-chloromethylpyridine hydroc~ oride, and following the pro-cedure described, 5-nitro~4-phenyl-3-(2-pyridylmethylthio)benzoic acid is obtained as a hemihydrate with a melting point of 235-237C (dec.).

B. 5-Amino-4-phenyl-3-~2-pyridylm-ethylthio)benzoic acid By replacing in Eximple 1, step ~, 3-benzylamuno-S~nitro-4-phenylbenzoic acid ~ith 5-nitro-4-phenyl-3-(2-pyridylmethyl~hio)benzoic ac~d, an~ following the procedure described, 5-amino-4-phenyl-3-(2-pyridylmet.~yl-thio)benzoic acid is obtained with a meltLng point of 210-211C.

C. 5-Chloro~ulfonyl-4-phenyl-3-(2-pyridyl~et~ylthio)benzoic acid ! By replacing in Example 1, ste~ F, S-amm D-3-benzylamino-4-~henyLbenzoic acid with an equimDlar amount of 5-amino-4-phenyl-3-(2-pyridyl-methylthio)benzoic acid, and following the procedure describ3d, 5-chloro-sulfonyl-4-phenyl-3-(2-pyridylmethylthio)benzoic acid is obtained.

1Q55~'~8 D. 4-Phen~1-3-~2-pyridvlmethylthio)-5-sulfamylhenzoi~ acid ~ replacing in Example 2, step F, 3-benzylox~-5-ahlorosulfonyl-4-pllenyLbenzoic acid with 5-chlorosulfonyl-4-~henyl-3-(2-pyridyLmet~ylthio)-benzoic acid, and foll~ing the proaedure descri~ed, 4-phe~Yl-3-(2-,~yridyl-me~ltl~io)-5-sulfamyLbenzoia acid i~ ~btained as a hy~rate ~ith a melting point of 83-86C.

Example 18 3-Benzylamino-4-phen~1-5-~ulf~myLben7Oic acid.
A. 5-Chlorosulfonyl-3-nitro-4-~-henyLbenzoic acid.
A hot .solution of 3-amms-5-nitro-4-phenyLbenzoic acid (7.8 g;
prepared as in Example 1, ste~ C) and notaqsium nitrite (3.0 g) in 1 .~l notassium hydroxide (50 ml) is added drol~wise to a mlxture of acetic acid (30 ml) and conc. hydrochloric acid (30 ml), while stirring vigorously at -2 to 2C. After additional stirring at this temperature for 10 minutes, the resulting diazoniumrsolution is added to a mixture of acetic acid t50 ml) saturated with 92 and cupric chIoride dihydrate (2.0 g) in water (4 ml).
~fter additional stirring for 2-3 hours, the precipitated 5-chlorosulfonyl-3-nitr~4-phenyLbenzoic acid is collected by filtration, ~7a~hed with ~7ater and dried.

~055~8 B. 3-Nitro-4-phenyl-5-sulfamylbenzoic acid.
By replacing in Example 1, step G, 3-benzylamLno-5-chlorosulfonyl-4-phenylbenzoic acid with 5-chlorosulfonyl-3-nitro-4-phenylbenzoic acid, and following the procedure described, 3-nitro-4-phenyl-5-sulfamylbenzoic acid is obtained as a hydrate with a melt mg point of 119-121C.

C. 3-A~ino-4-phenyl-5-sulfamyLbenzoic acid.
To a solution of 3-nitro-4-phenyl-5-sulfamylbenzoic acid (8.5 g) in acetic acid (100 ml), palladium (10%) on carbon (1.5 g) is added, and the muxture is hydrogenated~ After 2-2.5 hours the theoretical amDunt of hydrogen has been absorked, and the hydrogen uptake has subsided. The catalyst is removed by filtration, and the filtrate is evaporated in vacuo.
m e residue is recrystallized from acetic acid to give 3-amino-4-phenyl-5-sulfamylbenzoic acid with a melting point of 232.5-237C.

D. 3-~enzylanuno-4-phenyl-5-sulfa~ylbenzoic acid.
By replacing in Example 1, step D, 3-amino-5-nitro-4-phenylbenzoic acid with an equimolar amDunt of 3-amLno-4-phenyl-5-sulfamylbenzoic acid, and follcwing the procedure described, 3-benzylamlnL-4-phenyl-5-sulfamyl-benzoic acid is obtained with a melting point of 221-222C. m e material is identical (IR, analysis) with the material prepared as in Examçle 1, step G.

105~ ~4~
EC~MPLE 19 3-n-But _am mo-4-phenyl-5-sulfa~ benzoic acid.
A solution of 3-amino-4-p~enyl-5-sulfamylbenzoic acid (1.46 g) and n-butyl iodide (1.5 ml~ in n-butanol (20 ml) is refluxed for 3-4 days under such conditions,l that the water formed during the reaction i8 separated.
After 12, 24, 36 and 48 hours, additiona~ amounts of n-butyl iodide (each time 0.75 ml) are ad~ed. The resulting solution is evaporated ln vacuo, and the obtained crude n-butyl 3-n-butylamino-4-phenyl-5-sulfamyIbenzoate is saponified by heating with 2 N sodium hydroxide (20 ml~ for 30 minutes.
After cooling, the resulting solution is acidified with 4 N hydlochloric acid (12 ml) to precipitate 3-n-butylamino-4-phenyl-5-sulfamylbenzoic acid, which is aollected by filtration, washed with water and dried. After recrystalliza-tion fram agueous ethanol, the acid is obtained with a melting point of 134-136C.

EWqPLE 2?

3-AllYlamino-4-phenvl-5-qulfamYLbenzoic acid.
~ _ .. ,. . . , _ _ _ By replacing in Example 1, step D, 3-am m o-5-nitro-4-phenylbenzoic acid anl benzyl bromide with equimolar amounts of 3-aminD-4-phenyl-5-sul-famylbenzoic acid and allyl bromide respectively, and following the procedure described, 3-allylamino-4-phenyl-5-sulfamyIbenzoic acid is obtained with a melting point of 169-172.5C. _ 1~)5S~4~3 E~U~PLE 21 3-Crotylamino-4-phenyl-5-sulfamylbenzoic acid By replacing in ~xample 1, step D, 3-amino-5-nitro-4-phenylbenzoic acid and benzyl kromide with equimolar amounts of 3-amin~-4-phenyl-5-sulfamyl-benzoic acid and crotyl bromide respectively, and following the procedure described, 3-crotylamino-4-phenyl-5-sulfamylbenzoic acid is obtained with a nelting point of 186-1~7C.

3-(2-Furylmethylamino~-4-phenyl-5-sulfa~ylbenzoic acid To a solution of sodium methanolate (prepared from 0 12 g of sodium) in methan~l (15 ml), 3-amino-4-phenyl-5-sulfamyLbenzoic acid (1.46 g) is added followed by furfural (1.5 ml), and the resulting solution is refluxed for 20 hours. After cooling, sodium borohydride (1.5 g) is added in portions during about 1 h~ur, ~thile stirring at 0-5C. ~fter addition~l stirring at room temperature for 2 hours, the solvents are removed ln vacuo. The residue is dissolved in water (25 nl) and crude 3-(2-furylmethylamino)-4-phenyl-5-sulfamyIbenzoic acid is precipitated by acidification with acetic acid. m e crude acid is dissolved in hot saturated sodium hydrogen carbonate (15 ml), and the solution is filtered hot in the presence of decolorizing c~rbon. On cooling, the sodium salt separates. It is collected by filtration, 105~948 washed with a small amount of icecold water and dried. Th~ sodium salt is dissolved in hot water, and pure 3-(2-furylmethylamuno)-4-phenyl-5-sulfamyl benzoic acid is precipitated by acidification with acetic acid. m e acid is collected by filtration and is, after drying, obtained as a hydrate with a melting point of 167-169C.

EX~L~ 23 4-Phenyl-3-~4-pyridylethylamuno)-5-sulfamylbenzoic acid A solution of 3-amino-4-phenyl-5-sulfamylbenzoic acid (1.46 g), 4-vinylpyridine (1.0 ml) and acetic acid (0.5 ml) in methanol (7.5 ml) is refluxed for 5-6 hours. After cooling, the resulting solution is diluted with water (16 ml) to precipitate crude 4-phenyl-3-(4-pyridylethylamino)-5-sulfamyLbenzoic acid, which is collected by filtration, washed with water and dried. After recrystallization twice from aqueous ethanol, the acid is ob, tained with a melting point of 216.5-217.5C.

EXU~IPL~ 24 3-Benzylthio-4-phenyl-5-sulfamylbenzoic acid.
A. ~ EthyLxanthic acid 5-carboxy-2-phenyl-3-sulfamylphenyl ester.
To a ~ol~tion of 3-aminc-4-phenyl-5-sulfamylben20ic acid (1.46 g) in a mixture of acetic acid (10 ml) and oonc. hydrochloric acid (5 ml), a solution of sodium _ 1.05~4~
nitrite (0.35 g) in water t3.5 ml) is added dropwise, ~hile ~tirring at 0-5C.
The resulting diazonium-solution is carefully added in /small portions o a solution of pctassium ethyl xanthate (1.05 g) and sodium hydrogen carbonate (15 g) in water, t~hile stirring at 70-75C. When the nitrogen evolution has subsided, the resulti~g solution is cooled, and the ethylxanthic acid 5-car-boxy-2-phenyl-3-sulfamylphenyl ester is precipitated by acidification with 4 N hydrochloric acid.

B. 3-Benzylthio-4-phenyl-5-sulfamylbenzoic acid.
A mixture of ethylxanthic acid 5-carboxy-2-phenyl-3-sulfamylphenyl ester (2.0 g) and 2 N sodium hydroxide (20 ml) is heated on a steam bath for 1 hour, t~hile nitrogen is bubbled through ~he mLxture. After cooling, the resulting solution is acidified with 4 N hydrcchloric acid (12 ml) to precipitate crude 3-m~rcapto-4-phenyl-5-sulfamylbenzoic acid, which is col-lected by filtration, waghed with water and dried. me crude acid is in por-tions added to saturated sodium hydrogen carbonate (15 ml) follcwed by solid sodium hydrogen carbonate (1 0 g) and sodium dithionite (1.0 g). To the resulting solution, benzyl bromide (1.3 ml) is added, and ths mixture is stirred-at room temperature for 7-7 hours. After cooling, the precipitated sodium 3-benzylthio-4-phenyl-5-sulfamyl-1()5~94~
benzoate is collected by filtration, washed with a small am~unt of icecoldwater and dried. The sodium salt is dissolved in hot water, and the 3-benzylthio-4-phenyl-5-sulfamylbenzoic acid is precipitated by acidification with 4 N hydrochloric acid. The acid, is, after cooling, collected by fil-tration, washed with water and dried. After recrystallization from aqueous ethanol, it is obtained as a hemihydrate with a nElting point of 116-119C.
The material is identical (IR, analysis) with the material prepared as in Example lO, step E.

Claims (21)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. Process for producing a compound of the formula in which R1 represents a straight or branched unsubstituted alkyl containing 1 to 6 carbon atoms; a straight or branched unsubstituted alkenyl containing 2 to 6 carbon atoms; a straight or branched unsubstituted alkynyl containing 2 to 6 carbon atoms; or a methyl or ethyl radical substituted with phenyl, furyl, thienyl or pyridyl radical; Ar comprises a phenyl radical, Y comprises O, S, or NH;
YR1 is placed in the 2- or 3- position; or pharmaceutically acceptable non-toxic salts thereof; or pharmaceutically acceptable non-toxic esters thereof with cyano methanol, benzyl alcohol and C1 - C6 alkanols; which process comprises one of the following reactions:
(a) reacting a compound of the general formula or a salt or an ester thereof, wherein R1 and Y have the meanings defined above, and Hal comprises halogen, with ammonia; or (b) treating a compound of the general formula or an ester thereof, in which Ar and Y have the meanings defined above, with a compound of the formula R1Z, wherein R1 has the meaning defined above, and Z comprises a halogen atom, or an alkyl- or arylsulfonyloxy group, or with a di-R1-sulphate, a diazo compound of the formula R1N2or a quaternary ammonium compound of the formula R1N+(Alk)3, wherein R1 is as defined above, and Alk comprises alkyl having from 1 to 6 carbon atoms; or (c) subjecting a compound of the formula wherein Ar is as defined above and Y comprises NH, to a reductive alkylation using an aldehyde corresponding to R1 as defined above in having the same carbon atom content.

2. Process for producing a compound of the general formula Ia, Ia in which R1 represents a straight or branched unsubstituted alkyl containing 1 to 6 carbon atoms; a straight or branched unsubstituted alkenyl containing 2 to 6 carbon atoms; a straight or branched unsubstituted alkynyl containing 2 to 6 carbon atoms; or a methyl or ethyl radical substituted with phenyl, furyl, thienyl or pyridyl radical; Y stands for O, S, or NH; or pharmaceutically acceptable, non-toxic salts thereof; or pharmaceutically acceptable, non-toxic esters thereof with cyano methanol, benzyl alcohol and C1 - C6 alkanols; which comprises one of the following reactions:
(a) reacting a compound of the general formula IIa IIa or a salt or an ester thereof, in which R1 and Y have the meanings defined above, and Hal stands for halogen with ammonia;
(b) treating a compound of the general formula VIIIa VIIIa or an ester thereof, in which Y has the meaning defined above with a compound R1Z, in which R1 has the meaning defined above, and Z stands for a halogen atom, or an alkyl- or arylsulfonyloxy group, or with a di-R1-sulphate, a diazo compound of the formula R1N2, or a quaternary ammonium compound of the formula R1N+(Alk)3, R1 being defined as above and Alk standing for alkyl with from 1 to 6 carbon atoms; or (c) subjecting a compound of the general formula VIIIa, in which Y
stands for NH, to a reductive alkylation using an aldehyde corresponding to R1 in having the same carbon atom content.

3. The process of claim 2 wherein said reaction (a) is carried out in the presence of a suitable solvent, or in the presence of a com-pound capable of liberating ammonia.

4. The process of claim 3 wherein the suitable compound is water.

5. The process of claim 3 wherein the compound capable of liberating ammonia is an ammonium salt or is hexamethylene tetramine.

6. A process of claim 2 for preparing 3-benzylamino-4-phenyl-5-sulfamyl benzoic acid, or its pharmaceutically acceptable, non-toxic salt or its pharmaceutically acceptable, non-toxic ester which comprises reacting 3-benyzlamino-5-chlorosulfonyl-4-phenylbenzoic acid with ammonia.

7. A process of claim 1 for preparing 4-phenyl-3-(4-pyridyl-ethylamino)-5-sulfamylbenzoic acid, or its pharmaceutically acceptable, non-toxic salt or its pharmaceutically acceptable, non-toxic ester, which comprises reacting 3-amino-4-phenyl-5-sulfamylbenzoic acid with 4-vinyl-pyridine and acetic acid

8. A process of claim 2 for preparing 3-n-butoxy-4-phenyl-5-sulfamylbenzoic acid, or its pharmaceutically acceptable, non-toxic salt or its pharmaceutically acceptable, non-toxic ester, which comprises reacting 3-n-butoxy-5-chlorosulfonyl-4-phenylbenzoic acid with ammonium hydroxide.

9. A process of claim 2 for the preparation of 3-benzyloxy-4-phenyl-5-sulfamyl-benzoic acid or its pharmaceutically acceptable, non-toxic salt or its pharmaceutically acceptable, non-toxic ester, which comprises reacting 3-benzyloxy-5-chlorosulfonyl-4-phenylbenzoic acid with ammonia.

10. A process of claim 2 for the preparation of 5-chloro 4-phenyl-5-sulfamyl-benzoicacid or its pharmaceutically acceptable, non-toxic salt or its pharmaceutically acceptable, non-toxic ester, which comprises reacting 5-chlorosulfonyl-4-phenyl-3-(3-thenyloxy) benzoic acid with ammonia.

11. A process of claim 2 for the preparation of 3-n-butylthio-4-phenyl-5-sulfamyl-benzoic acid or its pharmaceutically acceptable, non-toxic salt or its pharmaceutically acceptable, non-toxic ester, which comprises reacting 3-n-butylthio-5-chlorosulfonyl-4-phenylbenzoic acid with ammonia.

12. A process of claim 2 for the preparation of 3-benzylthio-4-phenyl-5-sulfamyl-benzoic acid, or its pharmaceutically acceptable, non-toxic salt or its pharmaceutically acceptable, non-toxic ester, which comprises reacting 3-benzylthio-5-chlorosulfonyl-4-phenylbenzoic acid with ammonia.

13. A compound of the formula in which R1 represents a straight or branched unsubstituted alkyl containing 1 to 6 carbon atoms; a straight or branched unsubstituted alkenyl containing 2 to 6 carbon atoms; a straight or branched unsubstituted alkynyl containing 2 to 6 carbon atoms; or a methyl or ethyl radical substituted with phenyl, furyl, thienyl or pyridyl radical; Ar comprises a phenyl radical, Y comprises O, S, or NH;
YR1 is placed in the 2- or 3-position; or pharmaceutically acceptable, non-toxic salts thereof; or pharmaceutically acceptable, non-toxic esters thereof with cyano methanol, benzyl alcohol and C1 - C6 alkanols, whenever prepared or produced by the process of claim 1 or by its obvious chemical equivalent.

14. A compound of the formula wherein R1 represents a straight or branched unsubstituted alkyl containing 1 to 6 carbon atoms; a straight or branched unsubstituted alkenyl containing 2 to 6 carbon atoms; a straight or branched unsubstituted alkynyl containing 2 to 6 carbon atoms; or a methyl or ethyl radical substituted with phenyl, furyl, thienyl, or pyridyl radical; Y stands for O, S, or NH; or pharmaceutically acceptable, non-toxic salts thereof; or pharmaceutically acceptable esters thereof with cyano methanol, benzyl alcohol and C1 - C6 alkanols, whenever prepared or produced by the process of claim 2 or by its obvious chemical equivalent.

15. 3-Benzylamino-4-phenyl-5-sulfamylbenzoic acid or its pharmaceutically acceptable, non-toxic salts or its pharmaceutically acceptable, non-toxic esters, whenever prepared or produced by the process of claim 6 or by its obvious chemical equivalent.

16. 4-Phenyl-3-(4-pyridylethylamino)-5-sulfamylbenzoic acid or its pharmaceutically acceptable, non-toxic salts or its pharmaceutically acceptable, non-toxic esters, whenever prepared or produced by the process of claim 7 or by its obvious-chemical equivalent.

17. 3-n-Butoxy-4-phenyl-5-sulfamylbenzoic acid or its pharmaceutically acceptable, non-toxic salts or its pharmaceutically acceptable, non-toxic esters, whenever prepared or produced by the process of claim 8 or by its obvious chemical equivalent.

18. 3-Benzyloxy-4-phenyl-5- sulfamylbenzoicacid or its pharmaceutically acceptable, non-toxic salts or its pharmaceutically acceptable, non-toxic esters, whenever prepared or produced by the process of claim 9 or by its obvious chemical equivalent.

19. 5-Chloro-4-phenyl-5-sulfamylbenzoic acid or its pharmaceutically acceptable, non-toxic salts or its pharmaceutically acceptable, non-toxic esters, whenever prepared or produced by the process of claim 10 or by its obvious chemical equivalent.

20. 3-n-Butylthio-4-phenyl-5-sulfamylbenzoic acid or its pharmaceutically acceptable, non-toxic salts or its pharmaceutically acceptable, non-toxic esters, whenever prepared or produced by the process of claim 11 or by its obvious chemical equivalent.

21. 3-Benzylthio-4-phenyl-5-sulfamylbenzoic acid or its pharmaceutically acceptable, non-toxic salts or its pharmaceutically acceptable, non-toxic esters, whenever prepared or produced by the process of claim 12 or by its obvious chemical equivalent.